Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

AIMS: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. METHODS: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. RESULTS: Mean age at death was 68.2 years (range 49-96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aß IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. CONCLUSIONS: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

[Clinical and biomolecular classification of the frontotemporal dementias. A review of the literature]. / Clasificación clínica y biomolecular de las demencias frontotemporales. Revisión de la bibliografía.

INTRODUCTION: The term 'frontotemporal lobar dementia' (FTLD) covers a group of neurodegenerative diseases that are very heterogeneous in their clinical expression, genetic component and histopathological features, and this has traditionally made it difficult to study and classify them. Patients usually present a progressive change in their behaviour associated with language disorders and loss of memory, which constitutes the second most important cause of dementia in persons under the age of 65. The most significant characteristic at the histopathological level is the presence of abnormal aggregates or accumulations of proteins in neurons or glial cells; their identification has, on the one hand, helped further our knowledge of the pathogenic mechanisms and, on the other hand, has allowed this type of dementia to be classified. DEVELOPMENT AND CONCLUSIONS: In the last two decades a remarkable amount of progress has been made in our knowledge of this group of diseases, thanks to the genetic advances related to the discovery of the MAPT gene and the progranulin gene, as well as their mutations, which are responsible for a high percentage of cases of hereditary FTLD. Likewise, the development of new immunohistochemical techniques has made it possible to characterise some abnormal proteins, such as the protein TDP-43, as the main component of the neuronal inclusions in tau-negative FTLD. All this has led to a new classification of the FTLD. This work includes a thorough review of said advances and the possible clinical, histological, genetic and biomolecular correlations of the different subtypes of FTLD are also considered.

[Neuropathology of frontotemporal dementia].

Frontotemporal dementia (FTD) is a clinical phenotype of dementia, characterized by complex of clinical symptoms, including disinhibition, character change, increased appetite, sexual misconduct and language problems. Frontotemporal lobar degeneration (FTLD) is a pathological classification of neurodegenerative disorder and its core consists of Pick's disease (PiD). Historically, PiD was morphologically subclassified into three types, but recent immunocytochemical investigations defined type I as PiD with Pick bodies (three repeat tauopathy), type II as corticobasal degeneration (CBD, four repeat tauopathy) and type III as FTLD with ubiquitinated inclusions (FTLD-U). The recent progress provided an evidence that the majority of FTLD-U represented primary TDP 43 proteionopathy. Three major clinical phenotypes of FTLD consist of FTD, semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Clinical and pathological correlative studies demonstrated that majority of the background pathology of FTD is PiD with Pick bodies, that of SD is FTLD-U and that of PNFA is CBD, although there are too many exceptions. Although FTD is one of the major clinical manifestations of FTLD, the most frequent pathological background of FTD is Alzheimer disease (AD). The degenerative processes causing FTD symptoms include dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and argyrophilic grain disease. Moreover, vascular process such as Binswanger disease and inflammatory process such as neurosyphilis could also present with FTD symptoms. Since FTD requires special clinical care distinct from AD, clinical diagnosis of FTD is quite important. But for the fundamental treatment based on background pathological processes, surrogate biomarkers, including structural and functional neuroimages and findings of cerebrospinal fluid, blood and urine, should be pursued for future progress in FTD research.

[Current diagnostic, clinical and therapeutic conceptions of frontotemporal dementia]. / Wspólczesne koncepcje diagnostyczne, kliniczne i terapeutyczne otepienia czolowo-skroniowego.

The authors present a review of the selected publications on frontotemporal dementia. Frontotemporal dementia (FTD) is a progressive degeneration of the central nervous system. The typical symptoms of FTD are behavioural disorders, affective symptoms and speech disorders. Neuroimaging methods reveal atrophic lesions and hypometabolism of the frontal and temporal lobes.

Semantic dementia and primary progressive aphasia: a problem of categorization?

The relationship between semantic dementia (SD) and primary progressive aphasia (PPA) has been the subject of debate ever since the syndromes were first described, in converging streams of research from the neuropsychological and neurologic communities. The most salient clinical features of SD are anomia with circumlocution and semantic paraphasia, single-word comprehension deficit, and reduced category fluency. Of critical importance is the fact that patients also show deficits on non-verbal tasks using visual, auditory, and other modalities, suggesting that the key impairment in SD is a breakdown in conceptual knowledge rather than a specific problem with language. The finding of item consistency between the various tests supports this view. The order in which the features appear can be explained by the variable degree of redundancy in access to semantic knowledge from the different perceptual modalities. Atrophy is seen in the anterior and inferior temporal lobe rather than in classic language areas, further distancing SD from aphasic syndromes. Semantic dementia and progressive non-fluent aphasia (PNFA) share some clinical and pathologic characteristics with frontal variant frontotemporal dementia, but there are also clear differences between the three syndromes. We believe that many patients described as having fluent primary progressive aphasia in fact have early SD. Semantic dementia is a well-defined syndrome, distinct from PNFA but related to it within the spectrum of frontotemporal lobar degeneration syndromes.

Frontotemporal dementia--Part I. History, prevalence, clinical forms.

The authors report a comprehensive publication consisting of three parts going into the details of history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The first part of the present review deals with history, prevalence and clinical forms of FTD. The prototypical FTD with circumscribed atrophy was first described by Arnold Pick; Alois Alzheimer found the intraneural inclusions in the patients' brain. Later it was recognised that many patients had neither the atrophy nor the cellular changes, but genetic mutations have been identified. Frontotemporal dementia is a degenerative condition with unknown etiology in the frontal and anterior temporal lobes of the brain. It is a progressive neurobehavioral syndrome characterized by early decline in social interpersonal conduct, early impairment in the regulation of personal conduct, early emotional blunting, and early loss of insight. There are no reliable epidemiological studies on the prevalence of FTD, but it is well-accepted that FTD is a common cause for dementia before the age of 65 (it constitutes approximately five percent of all irreversible dementias). The nomenclature of the FTD has been confusing and continues to be. Three major clinical syndromes can be identified: 1 frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, 2. in semantic dementia (progressive fluent aphasia) there is a breakdown in the conceptual database which underlies language production and comprehension, 3. in progressive nonfluent aphasia the phonologic and syntactic components of language are affected. The authors report two cases, which can point to clinical symptoms and forms, and mention the problems of the differential diagnosis and therapy.

[Frontotemporal dementia. Results from "Frontotemporal Demential and Pick's Disease Conference"]. / Die frontotemporale Demenz. Ergebnisse der "Frontotemporal Dementia & Pick's Disease Conference"

At the Frontotemporal Dementia and Pick's Disease Conference, recent data concerning the epidemiology, diagnosis, and therapy of frontotemporal dementia were presented. Topics included clinical manifestations, differential diagnosis, pathologic and genetic bases of the disease, therapy, and specific problems facing patients and care givers. A consensus in the terminology of this condition was sought.

Evaluation of predictors of mortality in frontotemporal dementia-methodological aspects.

OBJECTIVES: To retrospectively evaluate pre-diagnostic clinical features (predictors) of mortality in frontotemporal dementia (FTD). The main aim was to investigate if there were indications against interpreting missing data as signs of absence. MATERIAL AND METHODS: 96 cases with FTD, here defined as Dementia in Pick's disease according to ICD-10. The predictors were behavioural/psychiatric features, language impairment and neurological deficits up to the date of diagnosis. Each predictor was rated as present (Yes), absent (No) or not recorded (Missing), and evaluated according to its distribution and mortality pattern: if a feature was not recorded because it was absent, the mortality of the Missing and the No-category should hypothetically be close. Statistical methods included Kaplan-Meier survival curves and Cox regression analyses. RESULTS: Neurological deficits and language impairments were frequently recorded as present or absent, while non-recordings were more prevalent among the behavioural/psychiatric features. Some features were excluded as predictors because they showed too little variation. Analyses of the survival pattern indicated that in some features, the observations of the Missing-category could be interpreted as absence of the symptoms. In other features these observations had to be regarded as truly missing. CONCLUSIONS: In the retrospective evaluation of predictors of mortality a method for treating missing data was applied. The interpretation of non-recordings as signs of absence was supported by the analyses of the survival patterns in some of the studied features. However, the study underscores the importance of systematic estimations of pre-diagnostic clinical features in dementia.

Pick's disease: a clinical overview.

What is to be understood by the term Pick's disease? Is this a clinical syndrome(s) of frontotemporal lobar atrophy, or a more specific clinicopathological concept of frontotemporal lobar atrophy with Pick bodies and/or Pick cells on neuropathology? The author discusses these concepts in an historical context as an introduction to this symposium.

Frontotemporal dementia (Pick's disease): clinical features and assessment.

The clinical presentation in frontotemporal dementia (FTD) reflects the distribution of the pathologic changes rather than the exact histologic subtype of the disease. Three major clinical syndromes can be identified: 1) frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology. Traditional cognitive tests are insensitive, but more specific measures are under development; 2) semantic dementia (progressive fluent aphasia) in which there is a breakdown in the conceptual database which underlies language production and comprehension, although deficits in nonverbal semantic knowledge can also be shown on neuropsychologic testing. Patients with semantic dementia have asymmetric anterolateral temporal atrophy with relative sparing of the hippocampal formation, which is typically worse on the left side. A variant of this syndrome affecting the right temporal lobe presents with progressive prosopagnosia; 3) progressive nonfluent aphasia in which the phonologic and syntactic components of language are affected in association with left peri-Sylvian atrophy. The assessment of patients with potential FTD involves a multidisciplinary approach. The development of comprehensive caregiver-based neuropsychiatric instruments, neuropsychologic tasks sensitive to semantic memory and other key cognitive impairments, and functional (hexamethyly-propyleneamine-SPECT) and structural (MRI) brain imaging represent significant advances in the field.

Neuropathology of Pick's disease.

The author reviews the gross, microscopic, and biochemical pathology associated with classic Pick's disease, as defined by Constantinidis' Type A Pick's disease. This is contrasted with other Pick's disease subtypes, including Constantinidis' Type B (corticobasal degeneration) and Type C (dementia lacking distinctive histology).

[New insights in frontotemporal dementia]. / Nieuwe inzichten in frontotemporale dementie.

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterised by progressive behavioural disturbance, aphasia and a decline in frontal cognitive functions. Frontotemporal atrophy on CT and MRI, and hypoperfusion of the frontal brain regions on single-photon emission computed tomography (SPECT), are characteristic findings. Neuropathological examination reveals deposition of abnormally phosphorylated tau protein in neurons and glial cells in a number of the sporadic and familial cases, while aspecific changes with neuronal loss, spongiosis and gliosis are found in the remaining cases. A familial form with an autosomal dominant pattern of inheritance is seen in 20% of FTD patients. Mutations in the tau gene have been identified in a number of families with deposition of abnormal tau protein in affected brain regions. Presymptomatic DNA testing is now available for relatives of patients with tau mutations, but must only be considered after extensive genetic counselling in a centre with neurogenetic expertise.

Volumetric study of lobar atrophy in Pick complex and Alzheimer's disease.

BACKGROUND: Lobar atrophy is an important neuroimaging feature of Pick complex (PiC). However, differences in patterns of focal brain atrophy between PiC and Alzheimer's disease (AD), and among PiC subgroups, have not been studied quantitatively. OBJECTIVE: To compare volumetric measures among primary progressive aphasia (PPA), frontotemporal dementia (FTD) and AD; to assess association between brain atrophy and cognition. PATIENTS: Seventeen patients with PPA, 11 with FTD and 24 with probable AD were studied. METHODS: We measured total and regional volume quantitatively using MRI and computerized volumetry. Contributing factors were controlled statistically or by adopting brain volume ratios. We investigated the classifying power of volumetry and correlated regional brain volume with cognitive and language test scores. RESULTS: The ratio for fronto-temporo-central region was smaller on the left in PPA and on the right in FTD. AD and some PPA patients had smaller parietal lobes. The frontal ratios correctly classified 93% of PPA and FTD patients, but only 50% of the entire PiC and AD patients. Language-dependent examinations correlated with the left fronto-temporal volume. CONCLUSIONS: Brain atrophy differs in PPA, FTD and AD, but there is some morphological overlap between PiC and AD in parietal volumes. Focal brain atrophy is most consistently associated with language impairments.